Lung cancer is a leading cause of cancer mortality, killing over 90,000 people each year in the U.S.. Smoking has shown the strongest association with lung cancer of the known risk factors. However, all individuals who smoke do not develop lung cancer. In the Johns Hopkins Lung Project (JHLP), over 5,000 men at high risk of developing lung cancer, i.e. 45 years of age or older who smoked 20 or more cigarettes per day, were screened using sputum cytology and chest x-ray at regular intervals for up to 8 years. The JHLP found that smokers who had persistent moderate atypia in sputum were at even greater risk of developing lung cancer than those who did not have atypia. The John Hopkins cytopathology laboratories are currently testing a battery of immunohistochemical markers in some lung cancer specimens. The study proposed here is designed to determine if there are biomarkers in the sputum of individuals with persistent moderate atypia or lung cancer which may serve as indicators for who will develop lung cancer. The full battery of 12 markers will be tested in the first phase, the developmental feasibility phase, of the study on the 27 subjects from the JHLP who had persistent moderate atypia (cases) and subjects from the JHLP who did not have persistent atypia (matched on age and smoking to cases) and coworkers of the cases matched on age who do not smoke. An index battery of a few biomarkers that is associated with lung cancer and atypia will then be identified and reduced from the full battery currently under study. This reduced battery will be derived by identifying markers that appear to distinguish subjects with lung cancer or persistent atypia from subjects without atypia or lung cancer. This index battery of biomarkers will then be applied in the second phase of the study to the previously obtained sputum specimens of a larger group, namely the 177 JHLP subjects who developed lung cancer, 177 JHLP subjects who had non-persistent moderate atypia and are matched on age and smoking to the cancer cases, and 177 non-smoking coworkers matched on age to the cancer cases. The latter two groups will also be followed to determine occurrence of atypia and cancer and will provide sputum at two points in time, one year apart, which will be tested using these biomarkers to see if they distinguish those who develop atypia and lung cancer.